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  Pharmaceutical compositions for the prevention and treatment of atherosclerosis and restenosis after ptcaUSPTO Application #: 20080107659Title: Pharmaceutical compositions for the prevention and treatment of atherosclerosis and restenosis after ptca Abstract: The present invention provides a pharmaceutical composition for the prevention or treatment of angiostenosis, comprising a compound inhibiting the function of midkine (MK) in blood vessel tissues as an effective ingredient. The present invention is useful for the prevention or treatment of angiostenosis attributed to arteriosclerosis or restenosis after percutaneous transluminal coronary angioplasty (PTCA). As compounds inhibiting the function of MK, antisense oligonucleotides that bind to a segment of a single-stranded mRNA transcribed from the MK gene to inhibit the synthesis of MK protein in cells, antibodies against the MK protein, and such can be used. (end of abstract)
Agent: Saliwanchik Lloyd & Saliwanchik A Professional Association - Gainesville, FL, US Inventors: Kenji Kadomatsu, Mitsuru Horiba, Takashi Muramatsu, Shinya Ikematsu, Sadatoshi Sakuma USPTO Applicaton #: 20080107659 - Class: 424158100 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Binds Hormone Or Other Secreted Growth Regulatory Factor, Differentiation Factor, Or Intercellular Mediator (e.g., Cytokine, Vascular Permeability Factor, Etc.); Or Binds Serum Protein, Plasma Protein, Fibrin, Or Enzyme The Patent Description & Claims data below is from USPTO Patent Application 20080107659. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to pharmaceutical compositions for the prevention and treatment of disorders attributed to intimal thickening, more specifically to pharmaceutical compositions for the prevention and treatment of these diseases, comprising MK or its inhibitor as an effective ingredient. BACKGROUND ART [0002] Incidence of ischemic cardiac diseases caused by arteriosclerosis, especially, coronary arteriosclerosis, such as angina pectoris, and myocardial infarction are recently on the increase. Pathological tissue images of arteriosclerosis mainly show local intimal thickening and diminished elasticity. As a result, circulation is disturbed, and nutrients and oxygen are insufficiently supplied to myocardial tissues, leading to the above-mentioned conditions. [0003] Many important findings have been made regarding the pathogenesis of intimal thickening. A typical example is that the thickened intima primarily constitutes of smooth muscle cells that migrated from tunica media (Parker, F., Amer. J. Pathol., 1960, 36, 19-53; and Webster, W. S., S. P. Bishop & J. C. Geer, Amer. J. Pathol., 1974, 76, 245-264). Moreover, the hypothesis that arteriosclerosis develops as a result of the injury-repairing reaction (Ross, R., N. Engl. J. Med., 1986, 314, 488-500) is the base of understanding on arteriosclerosis even now. [0004] Percutaneous transluminal coronary angioplasty (PTCA), a treatment in which a blood vessel constricted by such an intimal thickening is inflated by a balloon and physically expanded, is a common treatment at present. PTCA surgery has proved to be remarkably effective with a 90% or higher recovery rate. However, restenosis occurs with a frequency of 30 to 60% at the same site within 6 months or less following PTCA. It is pathologically recognized that restonis is the result of an excessive repairing mechanism, the excessive neointima formation at the artery wall of the injured site (Nobuyoshi, M. et al: J. Am. Coll. Cardiol. 17: 433-439, 1991). It has also been confirmed that this neointima forms from tunica media-derived smooth muscle cell migration and proliferation, and hyperplasia of the extracellular matrix. The following molecular biological mechanism in the neointima formation process is known. First, a transformation of blood vessel smooth muscle cells from a contractile to a synthetic phenotype is observed. Further, the following substances that induce cell proliferation, and overexpression of their receptors, have been reported: [0005] various growth factors, such as platelet-derived growth factor (PDGF) and Fibroblast growth factor (FGF); [0006] cytokines, such as interleukin and tumor necrosis factor .alpha. (TNF.alpha.); Angiotensin II; and Thrombin. [0007] Based on these backgrounds, it could be hypothesized that restenosis can be prevented by inhibiting the migration and proliferation of blood vessel smooth muscle cells. Thus, many pharmaceuticals were examined for their inhibitory effects on intimal proliferation using animal experiments. Effective ones were clinically tested, however, no effectiveness could be clinically established for any of these pharmaceuticals (Circulation., 1992, 86, 100-110; and Weint raub, W. S. et al., N. Engl. J. Med., 1994, 331, 1331-1337). [0008] Midkine (MK) was discovered as a gene product, expression of which is induced at the early stage of the differentiation induction process of embryonic tumor cells by retinoic acid (Kadomatsu, K. et al., Biochem. Biophys. Res. Commun., 1998, 151, 1312-1318). Pleiotrophin (PTN, or HB-GAM) was discovered as a binding protein having neurite elongation ability in the brains of newborn rats (Rauvala, H., 1989, EMBO J., 8, 2933-2941). MK and PTN are heparin-binding proteins which control cell proliferation, survival, and differentiation in the developmental process (Tomomura, M. et al., J. Biol. Chem., 1990, 265, 10765-10770; Li, Y. et al., Science, 1990, 250, 1690-1694; Rauvala, H., EMBO J., 1989, 8, 2933-2941; Wellstein, A. et al., J. Biol. Chem., 1992, 267, 2582-2587), have about a 50% sequence homology (Tomomura, M. et al., J. Biol. Chem., 1990, 265, 10765-10770; Kuo, M. et al., J. Biol. Chem., 1990, 265: 18749-18752; and Tsutsui, J. et al., Biochem. Biophys. Res. Commun., 1991, 176, 792-797), and form the MK family (Muramatsu, T., Dev. Growth Differ., 1994, 36, 1-8). [0009] A mature MK protein is a protein with a molecular weight of 13,000, comprising 121 amino acids rich in basic amino acids and cysteins. Its function is various, including, for example, promoting survival of nerve cells, neurite elongation, accelerating fibrinolysis in endothelial cells of blood vessels, and transformation of NIH3T3 cells. In addition to these, involvement of MK in tissue reconstitution has been recently drawing attention. Expression of MK was observed in gliocytes around brain infarction nidi, mainly in the epithelial side of the region where interaction between the epithelium and stroma takes place during development, etc. [0010] However, no relationship between arteriosclerosis and restenosis after PTCA and MK protein has been reported. DISCLOSURE OF THE INVENTION [0011] An objective of the present invention is to provide a novel drug for controlling neointima formation, especially to provide a novel drug effective for the treatment of arteriosclerosis and prevention of restenosis following PTCA surgery. [0012] The present inventors revealed a role for MK in neointima formation based on the following understandings. The results of RT-PCR and competitive PCR conducted on mRNA prepared from the blood vessel tissue of rat common carotid artery endothelium-injury model confirmed that the expression of MK mRNA was increased in the period from 7 to 10 days after injury. The neointima in the wild mice was remarkably enlarged compared with that in MK knockout mice in the neointima formation models prepared from the wild and MK knockout mice. Further, the injection of MK increased neointima size in MK knockout mice. [0013] Based on these findings, the present inventors proposed that MK has an important role in intimal thickening. The present invention revealed that inhibiting the function of MK in cells represses the corresponding proliferation-stimulatory activity, in which MK was involved, to prevent arteriosclerosis and restenosis after PTCA surgery, and completed the invention. [0014] Specifically, the present invention relates to the following pharmaceutical composition and a method for screening compounds for the pharmaceutical composition, namely to: (1) a pharmaceutical composition for the prevention or treatment of angiostenosis, comprising a compound inhibiting the functions of MK as an effective ingredient; [0015] (2) the pharmaceutical composition of (1), wherein the compound inhibiting the function of MK is an antisense oligonucleotide that inhibits intracellular MK protein synthesis by binding to a segment of a single-stranded mRNA transcribed from the MK gene; (3) the pharmaceutical composition of (1), wherein the compound inhibiting the function of MK is an antibody against the MK protein or a fragment comprising its variable region; (4) the pharmaceutical composition of (1), wherein angiostenosis is caused by arteriosclerosis or restenosis after PTCA surgery; (5) a method for screening a compound for the prevention or treatment of angiostenosis, comprising the steps of: (a) contacting MK expressing cells with a candidate compound; and, (b) selecting a compound inhibiting the function of MK; and, (6) a pharmaceutical composition for the prevention or treatment of angiostenosis, comprising a compound selected by the method of (5) as an effective ingredient. [0016] The present invention provides a pharmaceutical composition for the prevention or treatment of restenosis, comprising a compound inhibiting the function of MK as an effective ingredient. Alternatively, the present invention relates to the use of the compound inhibiting the function of MK in the prevention or treatment of restenosis. Moreover, the present invention relates to the use of a compound inhibiting the function of MK in the production of a pharmaceutical composition for the prevention or treatment of restenosis. Continue reading... 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